DESCRIPTION (taken from application) The candidate is currently a Clinical Instructor in Medicine and a Fellow in the UCSF Molecular Medicine Training Program. His long-term career goal is to become a productive biomedical investigator with an independent research program focused on the development of novel and clinically-applicable gene delivery systems for hepatic gene therapy. Towards this goal, the candidate has developed, along with his Research Mentor, Dr. Y.W. Kan, a structured career development program that incorporates a supervised research curriculum as well as graduate course work and specialized workshops. The candidate's research proposal explores two novel strategies for hepatic gene delivery, one based on retroviral vectors and the other on adenoviral vectors. The ability to efficiently and selectively deliver therapeutic genes to hepatocytes in vivo would represent a major advance in the treatment of both hereditary and acquired diseases of the liver. Unfortunately, none of the delivery systems currently available results in expression which is liver-specific, efficient and long-lasting. Gene delivery via retroviral vectors, the strategy most commonly employed in clinical trials, results in stable integration of genes, thus permitting long-lasting expression, but the current generation of retroviral vectors is neither targeted nor efficient. The candidate plans to design, engineer, and test retroviral vectors that are both efficient and hepatocyte-specific as part of the research plan. His hypothesis, which is based conceptually on extensive work done in the laboratory of the mentor, is that specific targeting and enhanced efficiency of retroviral vectors can be achieved through the purposeful manipulation of ligand-receptor interactions. In order to test this hypothesis, the candidate plans to redirect the tissue tropism of retroviral vectors by engineering into their envelope proteins ligands that bind specifically to receptors on hepatocytes. In studies complementary to these, the candidate will also test whether focused immunomodulation using a recombinant fusion protein, CTLA4Ig, that he has designed and constructed will specifically subvert the destructive immune responses that thwart adenoviral gene delivery. These studies, performed in an outstanding research environment as part of a structured career development program, will provide the technical research skills, theories and conceptualizations that the candidate will need to launch an career as an independent investigator.